The Evolving Therapeutic Landscape for Marginal Zone Lymphoma: Expert Perspectives

SAMEH GABALLA, MD, MSc

Assistant Professor, University of South Florida

Assistant Member, Department of Malignant Hematology

H. Lee Moffitt Cancer Center & Research Institute

Tampa, FL

ARIELA NOY, MD

Medical Oncologist, Hematologic Malignancies/Lymphoma Service

Memorial Sloan Kettering Cancer Center

New York, NY

INTRODUCTION

Editors from OncLive^® spoke with lymphoma experts Sameh Gaballa, MD, MSc, and Ariela Noy, MD, for their insights on recent advancements in the treatment of marginal zone lymphoma (MZL), the effect of Bruton tyrosine kinase (BTK) inhibitors (BTKis) on the therapeutic landscape, unmet therapeutic needs and clinical study challenges, and potential therapies of interest for the future.*

*Interview transcripts are slightly edited for readability.

OncLive^®: What do you think are the most important recent developments in the treatment of MZL?

SAMEH GABALLA, MD, MSc: Most recently, [MZL] has had some interesting approvals [of new treatments]. We have umbralisib, a novel PI3Ki that inhibits PI3Kδ and PI3Kε, which decreases the immune-mediated toxicities [associated with PI3Kis].

Another recent and interesting addition was zanubrutinib, which seems to have more specific BTK targeting than ibrutinib. This translates to fewer off-target [adverse] effects [AEs], [such as] less atrial fibrillation and less elevated blood pressure. There are still bleeding-associated AEs with zanubrutinib, but [other AEs], such as skin rash and atrial fibrillation, are [less frequent].

We need long-term data, because with ibrutinib, we have [extensive] data, especially from studies of chronic lymphocytic leukemia [CLL], whereas zanubrutinib is still relatively new. Data from the MAGNOLIA clinical trial [NCT03846427], which studied patients with relapsed or refractory (R/R) MZL, looked very interesting to me. Overall responses were about 70%, with a quarter of these patients getting a complete response, which is pretty impressive in that setting. The question going forward is: what are the next steps? Should combinations [of zanubrutinib] be explored? Should [zanubrutinib] be studied in the first-line setting?

Lastly, chimeric antigen receptor [CAR] T-cell therapy is also [a potential treatment] on the horizon. We don’t have a lot of [MZL] data as of yet; the ZUMA-5 clinical trial [NCT03105336] has more data on follicular lymphoma [FL]. But it’s hard to make conclusions based on ZUMA-5, because the number of patients studied were few. It is possible the toxicity seemed to be high, because [the study size was small]. Progression-free survival [PFS] might not be as good as [observed in studies with other agents,] but, again, there were very few patients. We really need to get more data to clarify the role of CAR T-cell therapy in MZL.

ARIELA NOY, MD: Before 2017, the [treatment] paradigm for MZL mirrored [that of] FL. The change in 2017 was that we learned that BTKis are active in MZL, though not in FL, which was clearly a surprise. We now have drugs that are available to use that have better toxicity profiles than PI3Kis.

OncLive^®: What are some of the challenges associated with clinical trials for MZL?

NOY: MZL is not one uniform disease. We have patients [with] mucosa-associated lymphoid tissue [MALT] lymphoma, splenic MZL, or nodal MZL. With time, individual patients may experience changes [in their disease]. [At first, their disease may be] primarily splenic, and then they get a splenectomy or rituximab, and now they have nodal disease. This makes it difficult to interpret who [is] participating in the trial.

As with FL, when we say someone has an indication for therapy, what does that mean? It means different things to different investigators. I might see a patient and say, “In light of this and that, I feel comfortable continuing to monitor you.” Someone else might say, “You need treatment right away.”

We have guidelines. We have the original guidelines from the French study group, and we have the guidelines from the National Comprehensive Cancer Network. However, those are [only] guidelines. When we put patients into a trial, it’s probably important to have a checkbox stating why I’m including a patient into the trial so I don’t have to go back later and try to figure it out.

Sometimes, it’s obvious. If someone has autoimmune hemolytic anemia, and their hemoglobin [level] is 7, you don’t have to scratch your head. But do you know what progressive disease means and how that, as an indication, is less concrete to characterize when we start a study? [This] makes cross-trial comparisons exceptionally difficult.

OncLive^®: How have BTKis impacted the treatment paradigm for MZL?

NOY: BTKis are very powerful in the treatment of MZL. We see response rates that have clinically significant meaning to patients, and PFS can be long, especially in patients [who] have only had rituximab.

As we just saw in a trial of patients with previously treated CLL that compared acalabrutinib with ibrutinib [NCT02477696], [second-generation BTKis] have better AE profiles. There were fewer treatment discontinuations in the acalabrutinib arm [than the ibrutinib arm]. Some AEs are really bothersome to patients.

[For example,] even grade 2 diarrhea can severely impact [a patient’s] life. If you are one of those patients that has one of those AEs, it is a problem. We might end up seeing more patients being treated with alternative [therapies], but they will still be considered for BTKis.

OncLive^®: What are some of the unmet needs that still exist in the treatment of MZL? Could these unmet needs be addressed with therapies that are currently available, or are there any investigational agents in the pipeline that could fill these gaps?

GABALLA: The main unmet need right now is for first-line treatments. We have single-agent rituximab, but for patients who have bulky disease, the most commonly used regimen is really bendamustine-rituximab, which is chemotherapy. We need something that is not chemotherapy to use in the frontline setting. I think BTKis or even PI3Kis could be considered in this setting.

I like the safety profiles of BTKis more than [those of] PI3Kis, even with umbralisib coming on board. PI3Kis seem more toxic than BTKis. There are still incidences of grade 2 diarrhea and grade 3 or 4 liver toxicities [with BTKis], but, [when] compared with PI3Kis, the safety profiles of BTKis are still better.

BTKis should be explored more in the frontline setting, possibly in combination with other agents, such as rituximab.

OncLive^®: Are there any clinical trials for treatment of MZL that have the potential to be practice-changing for clinicians who treat this disease?

GABALLA: There is an investigator-initiated [and] multicenter clinical trial, led by Memorial Sloan Kettering [NCT04212013], that is currently enrolling patients with [untreated] MZL to compare ibrutinib combined with rituximab [with] rituximab [monotherapy]. I think that is going to be an interesting trial.

I’m also interested in more studies about the role of CAR T-cell therapy in MZL.

Lastly, there are [new] BTKis—for example, LOXO-305 [pirtobrutinib]. At some point, we will need to study its safety and efficacy in MZL. There is definitely going to be more interesting data coming out over the next few years.

NOY: CAR T-cell therapy and allogenic stem cell transplantation [ASCT] are the only known curative options, but they are expensive, and they have very severe AEs. [These AEs] are not only immediate in the first 30 [through]100 days, but also in terms of lifelong potential effects. Patients treated with ASCT and CAR T-cell therapies experience at least 1 year of profound immunosuppression.

That is not an option for everyone. If we had something that was in between [noncurative and curative], that would be interesting. One of the questions is: could bispecific antibodies bridge that gap? Could a patient be treated with a bispecific antibody and not experience as severe immunosuppression as [they would with] CAR T-cell therapy?

The toxicities of some of the new CAR T-cell therapies will be less in terms of cytokine release syndrome. May be these could be curative options for patients with MZL.

OncLive^®: Are there any other important issues of which clinicians should be aware?

NOY: COVID-19 vaccinations for patients receiving treatment for MZL have been really challenging. There have been patients who were on a relapse treatment, and we decided to give them maintenance. We had to stop maintenance. [We did not know] how BTKis and PI3Kis [affect] immune response to vaccines. Some patients needed third vaccines and still didn’t respond. That remains a very challenging area.

[Also], some drugs are labeled as an indefinite therapy. We don’t know anything about who can safely discontinue treatment. We are seeing that clinically, because some patients discontinue because of AEs and retain their remission.

So is it possible to treat someone for a fixed amount of time to obtain a certain depth of response, discontinue, and then restart the drug a year or 2 later or maybe longer? We really don’t know.